While the involvement of in utero exposure to first-hand smoke (FHS) and second-hand smoke (SHS) in the pathogenesis of thrombotic diseases is well documented, the contribution of the newly ?discovered? third-hand form (THS) in such disease processes remains unknown. This derives, in part, from: (1) initial lack of knowedlge of THS existence; (2) lack of appreciation for its ?real? negative health consequences; (3) lack of a THS-exosure animal model that mimics real-world scenarios; and (4) lack of studies regarding such consequences on platelet biology. The present application proposes experiments that address fundamental, mechanistic, epigenetic and clinically-relevant translational aspects of the adverse-health effects of the newly ?realized? form of smoking, THS, in utero and in the context of thrombotic disease and platelet biology, and gender. Studies are also proposed to investigate, in a similar fashion, the toxicants that underlie THS effects on platelets and associated diseases. These studies are of paramount significance given that the dangers of THS are underestimated/unappreciated, despite evidence that it is more toxic than SHS, especially in vulnerable populations such as children and minorities (e.g., Hispanic Americans). The Aims of our proposal are: Aim 1. Investigate the impact of in utero THS-exposure on platelet-dependent diseases. While in utero exposure to the well-known FHS and SHS was found to contribute to the genesis of myocardial infarctions, whether in utero exposure to THS is also associated with an increased risk of thrombotic disorders, is yet to be determined. To address this issue, we will determine the ramifications of in utero THS exposure on normal hemostasis, platelet counts, as well as on clotting factors and other thrombosis mediators, in a dose-, and time- dependent fashion. Subsequent studies will examine whether in utero THS participates in the development of thrombotic disorders. Aim 2. Investigate the mechanism by which in utero THS-exposure modulates platelet function. Our recently published findings show, for the first time, that adult THS exposure modulates physiological hemostasis, and increases the risk of thrombogenesis, via enhancing platelet activation. However, whether in utero THS is associated with similar effects, and if so, the mechanism by which it modulates platelet function remain to be investigated. Thus, the overall goal of the experiments proposed in this section is to determine the significance, toxicants and mechanism of the impact of in utero THS-exposure on various platelet functional responses, platelet epigenetics, its effect on other blood cells (e.g., leukocytes) and thrombosis ?markers?, as well as its major route of exposure. Collectively, these experiments will make significant contributions to our understanding of the consequences of in utero THS exposure on platelet activation and cardiovascular human health, its epigenetics, and the mechanism and toxicants by which THS exerts its effects.